- Diversity & Inclusion
- Contact Us
Pharmacology and Molecular Sciences
725 N. Wolfe St.
Baltimore MD 21205
Chemical biology and molecular biology; use of small molecules to probe important cellular processes and pathways; translational medicine
Our primary research interest lies at the interface between chemistry, biology and medicine. We seek to discover new chemical ligands to modulate signaling pathways and cellular processes of interest by conducting high-throughput screening of chemical libraries we generate or assemble. The newly discovered ligands will then be used to probe the signal transduction pathways and cellular processes with which they interfere using a combination of experimental methods from synthetic chemistry to molecular and cellular biology to structural biology. The new insights we gain through this exercise not only throw new lights on the pathways and processes under scrutiny but also pave the way for the new chemical probes to becoming new drug leads.
We have been assembling and generating unique chemical libraries as sources for small bioactive chemical probe discovery. Over 16 years ago, we began an initiative to collect and assemble a library of known drugs approved by US FDA and its foreign counterparts that led to the establishment of the Johns Hopkins Drug Library (JHDL). The library has been made available free of charge to the entire Johns Hopkins community and to other researchers around the globe at low cost. We and our collaborators have screened JHDL in a large number of cell- and target-based assays and identified many new cellular and pharmacological activities among existing drugs. The newly identified activities among known drugs served as launching pads for new investigation into the underlying molecular mechanism of action for the new activities on the one hand, and translation of the discoveries into new clinical applications on the other. An illuminating example in this drug-repurposing endeavor is the identification of novel anti-angiogenic and anti-hedgehog activities of the widely used antifungal drug itraconazole. Our ensuing mechanistic studies of the antiangiogenic mechanism of itraconazole unraveled two previously unknown molecular targets of itraconazole in human cells, the voltage-dependent anion channel (VDAC)1 on the outer mitochondria membrane, and the Niemann Pick type C (NPC)1, a cholesterol transporter on the surface of endolysosome. We subsequently showed that binding of itraconazole to VDAC1 causes a decrease in cellular ATP levels, leading to the corresponding increase in cellular AMP-to-ATP ratio and activation of AMPK, leading to inhibition of mTOR. We also found that binding of itraconazole to NPC1 causes accumulation of cholesterol and phospholipid in the endolysosome, impairing lysosomal calcium signaling that is required for mTOR activation. The concurrent inhibition of VDAC1 and NPC1 by itraconazole leads to synergistic inhibition of mTOR. In collaboration with physician scientists at Hopkins and elsewhere, we have also been engaged in validating the anti-angiogenic activity of itraconazole in both preclinical and clinical settings. Currently, itraconazole and its improved analog with reduced toxicity are undergoing Phase 1 and 2 human clinical trials for treating a variety of cancers, including basal cell carcinoma, prostate and lung cancer.
In more recent years, we have created a new type of macrocycle library called rapafucins that was inspired by the unique structure and extraordinary mode of action of the mTOR inhibitor rapamycin. A unique feature of rapafucins is that they are capable of recruiting FKBP proteins to their cellular and pharmacological advantage. Most importantly, they are uniquely effective in binding to membrane proteins and in disrupting protein-protein interactions. We have designed and synthesized a 45,000-compound rapafucin library and screened it in a number of distinct cell- and target-based assays. We have discovered highly potent and specific inhibitors for different isoforms of glucose transporters that are intimately involved in mediating the Warburg effect in cancer cells, inhibitors of Yes-associated protein (YAP) downstream of the Hippo signaling pathway, and novel agonists of the mechanosensing signaling pathway leading to YAP activation with implications in stem cell pluripotency and tissue/organ regeneration, to name a few. Many of the optimized rapafucin inhibitors showed efficacy in appropriate animal models of human disease from cancer to heart regeneration. We are continuing to refine and expand the structural diversity of the rapafucins and to discover new cellular and pharmacological activities of the rapafucins.
McClary, B, Zinshteyn, B, Meyer, M, Jouanneau, M, Pellegrino, S, Yusupova, G, Schuller, A, Reyes, JCP, Lu, J, Guo, Z, Ayinde, S, Luo, C, Dang, Y, Romo, D, Yusupov, M, Green, R, Liu, JO. (2017) Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A. Cell Chem Biol, 24, 605-613.
Head, SA, Shi, W. Q, Yang, EJ, Nacev, BA, Hong, SY, Pasunooti, KK, Li, RJ, Shim, JS, and Liu, JO. (2017) Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis. ACS Chem Biol, 12, 174-182.
He, QL, Minn, I, Wang, Q, Xu, P, Head, SA, Datan, E, Yu, B, Pomper, MG, Liu, JO. (2016) Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation. Angew Chem Int Ed, 55, 12035-12039.
Li, RJ, Xu, J, Fu, C, Zhang, J, Zheng, YG. Jia, H, Liu, JO. (2016) Regulation of mTORC1 by lysosomal calcium and calmodulin. Elife, 5, e19360
Head, SA, Shi, W, Zhao, L, Gorshkov, K, Pasunooti, K, Chen, Y, Deng, Z, Li, RJ, Shim, JS, Tan, W, Hartung, T, Zhang, J, Zhao, Y, Colombini, M, Liu, JO. (2015) Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. Proc Natl Acad Sci USA, 112, E7276-7285.
Titov, DV, Gilman, B, He, QL, Bhat, S, Low, WK, Dang, Y, Smeaton, M, Demain, AL, Miller, PS, Kugel, JF, Goodrich, JA, Liu, JO. (2011) XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol, 7, 182-188.
Schneider-Poetsch, T, Ju, J, Eyler, DE, Dang, Y, Bhat, S, Merrick, WC, Green, R, Liu, JO. (2010) Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat Chem Biol, 6, 209-217.
Kim, J, Tang, JY, Gong, R, Kim, J, Lee, JJ, Clemons, KV, Chong, CR, Chang, KS, Fereshteh, M, Gardner, D, Reya, T, Liu, JO, Epstein, E. H., Stevens, D. A., Beachy, P. A. (2010) “Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth.” Cancer Cell, 17, 388-399.
Pan, F, Sun, L, Dardian, DB, Whartenby, KA, Pardoll, DM, Liu, JO. (2007) Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin. Nature, 445, 433-436.
Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Jr., Liu JO. (2007) Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol, 2, 263-70.
Chong, CR, Chen, X, Shi, L, Liu, JO, and Sullivan, DJ. (2006) A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol, 2, 415-416.